Myeloma, also termed as plasmacytoma and multiple myeloma, is a neoplastic disease characterized by the accumulation of monoclonal plasma cells in the bone marrow. Myeloma is a disease in which terminally differentiated B cells or plasma cells that produce and secrete immunoglobulins are monoclonally increased predominantly in the bone marrow, and thereby monoclonal immunoglobulins or their constituent light chains or heavy chains are detected in the blood of patients with this disease.
For the treatment of myeloma, chemotherapeutic agents have so far been used, but no effective therapeutic agents have been discovered that lead to complete remission of the disease and that prolong the survival period of patients with myeloma, and thereby the appearance of drugs that have therapeutic effects of myeloma have long been sought after.
On the other hand, Goto, T. et al. have reported a monoclonal antibody (mouse anti-HM1.24 antibody) that was obtained by immunizing mice with human myeloma cells (Blood (1994) 84, 1922-1930). When anti-HM1.24 antibody was administered to a mouse transplanted with human myeloma cells, the antibody accumulated in tumor tissues in a specific manner (Masaaki Kosaka et al., Nippon Rinsho (Japan Clinical) (1995) 53, 627-635), suggesting that anti-HM1.24 antibody could be applied in the diagnosis of tumor localization by radioisotopic labeling, missile therapies such as radiotherapy, and the like.
In the above Blood (1994) 84, 1922-1930, it has been described that anti-HM1.24 antibody has an in vitro cytotoxic activity on a human myeloma cell line RPMI8226. It has also been shown that chimeric anti-HM1.24 antibody that is mouse anti-HM1.24 antibody turned chimeric, and a humanized reshaped anti-HM1.24 antibody specifically bind to myeloma cells and have a cytotoxic activity (Blood (1999) 93, 3922-3920).
Thus, HM1.24 antigen has been highly expressed specifically on myeloma cells that are terminally differentiated B cells and, as the anti-HM1.24 antibody that recognizes this antigen exhibits a cell-killing activity in proportion to the number of HM1.24 molecules on the cell surface, an immunotherapy employing anti-HM1.24 antibody is thought to be an effective method of treating multiple myeloma. Thus, if the amount expressed of HM1.24 antigen, an antigen of anti-HM1.24 antibody, on the cell surface could be enhanced, the administration of a smaller amount of the antibody is expected to provide an equal cytotoxic activity thereby lowering side effects.
On the other hand, interferon was discovered to be a substance that exhibits a suppressing activity of viral growth and is known to be classified into four groups of α, β, γ, and ω and to have a variety of biological activities (Pestka, S., et al., Ann. Rev. Biochem. (1987) 56, 727-777; Langer, J. A., et al., Immunology Today (1988) 9, 393-400). However, there were no reports on the fact that interferon-α and interferon-γ had an effect of increasing the amount expressed of HM1.24 antigen in myeloma cells.
On the other hand, interferon regulatory factor (IRF)-1 and -2 were identified as transcription regulatory factors of the IFN-β gene. IRF-1 and -2 are known to bind to the same gene regulatory sequence: IRF-1 and IRF-2 act in an antagonistic manner in that IRF-1 acts as a transcription activation factor, whereas IRF-2 acts as a transcription suppressing factor. The NIH3T3 cells in which IRF-2 was highly expressed have been demonstrated to exhibit enhanced cell saturation density, colony formation in the methylcellulose gel, and a tumorigenic property in nude mice, and IRF-2 acts as an oncogene.
On the other hand, recent advances in research have indicated that IRF-2 is required for the expression of histone H4 that acts to control the cell cycle. IRF-2 is also shown to increase the expression of vascular cell adhesion molecule-1 (VCAM-1) in muscle cells, and it is becoming increasingly clear that the acid region (182 to 218) is involved in the activation of VCAM-1. Based on this, it is known that IRF-2 not only acts as a transcription regulatory factor but as a transcription activation factor.
However, it was not known that IRF-2 protein binds to the promoter (HM1.24 promoter) of the HM1.24 antigen gene, and activates said promoter.